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Author Notes:

To whom correspondence should be addressed. E-mail: david.lynn@emory.edu

Edited by Harry B. Gray, California Institute of Technology, Pasadena, CA, and approved June 26, 2007

Author contributions: J.D., A.K.M., W.S.C., J.A.S., Z.M., R.A.S., K.W., and D.G.L. designed research; J.D., J.M.C., J.E.S., B.T., W.S.C., J.A.S., and K.W. performed research; J.D., J.M.C., A.K.M., J.E.S., B.T., W.S.C., J.A.S., Z.M., R.A.S., K.W., and D.G.L. analyzed data; and J.D., A.K.M., W.S.C., J.A.S., Z.M., K.W., and D.G.L. wrote the paper.

We thank James Lah and Craig Heilman for initial neurotoxicity assays, Yi Xu and Rong Ni for assistance with peptide synthesis and purifications, and C. L. Emerson for AFM instrumentation.

The Stanford Synchrotron Radiation Laboratory is a national user facility operated by Stanford University (Stanford, CA) on behalf of the U.S. DOE, Office of Basic Energy Sciences. The SSRL Structural Molecular Biology Program is supported by DOE, Office of Biological and Environmental Research and by the NIH National Center for Research Resources and Biomedical Technology Program.

AA analysis was performed by the Keck Biotechnology Resource Laboratory at Yale University (New Haven, CT), and ICP-MS was performed at the Chemical Analysis Laboratory at the University of Georgia.


Research Funding:

This work was supported by Department of Energy (DOE) Grant ER15377 (to D.G.L.), National Institutes of Health (NIH) National Institute of General Medical Sciences Grant GM42025 (to R.A.S.), NIH Grants AG 023695 and NS 048254 and the R. W. Woodruff Health Sciences Center Fund (to Z.M.), Emory Alzheimer's Disease Center Grant P50 AG025688 (to D.G.L. and Z.M.), and National Science Foundation Grant CHE-0131013 (for CD instrumentation).


  • copper-binding
  • neurotoxicity
  • self-assembly

Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity

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Journal Title:

Proceedings of the National Academy of Sciences


Volume 104, Number 33


, Pages 13313-13318

Type of Work:

Article | Post-print: After Peer Review


Protein and peptide assembly into amyloid has been implicated in functions that range from beneficial epigenetic controls to pathological etiologies. However, the exact structures of the assemblies that regulate biological activity remain poorly defined. We have previously used Zn2+ to modulate the assembly kinetics and morphology of congeners of the amyloid β peptide (Aβ) associated with Alzheimer's disease. We now reveal a correlation among Aβ-Cu2+ coordination, peptide self-assembly, and neuronal viability. By using the central segment of Aβ, HHQKLVFFA or Aβ(13–21), which contains residues H13 and H14 implicated in Aβ-metal ion binding, we show that Cu2+ forms complexes with Aβ(13–21) and its K16A mutant and that the complexes, which do not self-assemble into fibrils, have structures similar to those found for the human prion protein, PrP. N-terminal acetylation and H14A substitution, Ac-Aβ(13–21)H14A, alters metal coordination, allowing Cu2+ to accelerate assembly into neurotoxic fibrils. These results establish that the N-terminal region of Aβ can access different metal-ion-coordination environments and that different complexes can lead to profound changes in Aβ self-assembly kinetics, morphology, and toxicity. Related metal-ion coordination may be critical to the etiology of other neurodegenerative diseases.

Copyright information:

© 2007 by The National Academy of Sciences of the USA

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